Preparation of Carboxylic Acid Anhydrides

Nucleophilic substitution in acyl chlorides is much faster than in alkyl chlorides. 

The ip -hybridized carbon of an acyl chloride is less stericaUy hindered than the sp -hybridized carbon of an alkyl chloride, making an acyl chloride more open toward nucleophilic attack. Also, unlike the Sn2 transition state or a carbocation intermediate in an SnI reaction, the tetrahedral intermediate in nucleophilic acyl substitution has a stable arrangement of bonds and can be formed via a lower energy transition state. 

After acyl halides, acid anhydrides are the most reactive carboxylic acid derivatives. Three of them, acetic anhydride, phthalic anhydride, and maleic anhydride, are industrial chemicals and are encountered far more often than others. Phthalic anhydride and maleic anhydride have their anhydride function incorporated into a ring and are referred 

The customary method for the laboratory synthesis of acid anhydrides is the reaction of acyl chlorides with carboxylic acids (Table 20.2). 

This procedure is applicable to the preparation of both symmetrical anhydrides (R and R the same) and mixed anhydrides (R and R different). 

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Preparation of carboxylic acid anhydrides. Adkins and Thompson found that addition of furoyl chloride to a solution of pyridine in petroleum ether at —20° results in separation of an analytically pure i I addition complex, m.p. about 60° dec. The complex reacts with 0.5 mole of water in benzene or dioxane to give the anhydride. Benzoic anhydride was obtained in this way in 97% yield. The anhydride can be obtained also by reaction of the complex with 1 mole of the free acid. This method was used in the preparation of heptoic anhydride. Addition of the acid... 

General method for preparation of carboxylic acid anhydrides... 

PREPARATION OF CARBOXYLIC ACIDS, ACID HALIDES, AND ANHYDRIDES... 

Thiol carboxylic esters (1) are the most common compounds among the three types of thioester. They are activated derivatives of carboxylic acids and exhibit acylating properties similar to those of carboxylic acid anhydrides. They have therefore found widespread application in synthetic chemistry and have been used for preparing esters, amides and peptides, especially macrocyclic ketones and lactones. Several review articles concerning the chemistry of thiol carboxylic esters - - and thiol lactones have appeared. 

Adducts (6) and (7) from amides and chlorophosphoric acid aiyl esters or dichlorophosphoric acid aryl esters respectively are well known. - The adducts are formed in a 1 1 ratio. They have been applied to the synthesis of mixed anhydrides from diarylphosphoric acids and carboxylic acids, as well as mixed substituted esters of pyrophosphoric acid. The adduct formation between primary or secondary carboxamides and dichlorophosphates has been used to prepare nitriles and isonitriles respectively. The adduct from DMF and phenyldichlorophosphate is a useful reagent for the preparation of carboxylic acid esters from the corresponding acids and alcohols, 3-lactams from imines and carboxylic acids," carboxylic acid anhydrides, carboxylic acid esters and thiol esters. Adducts of amides with ester amides or diamides of chlorophosphoric acid have been studied. ... 

A polymeric HOBt (132), which is soluble in dichloromethane, DMF or water and bears a poly (ethylene glycol) (PEG) chain (average molecular wt 4000), has been prepared from PEG-NH2 and l-hydroxybenzotriazole-5-carboxylic acid using DCC as coupling agent [135]. The corresponding active esters were prepared by reaction with an excess of carboxylic acid anhydrides and used for the synthesis of the model tetrapeptide Cbz-Leu-Ala-Gly-Val-OtBu [136]. 

N,N-disubstituted acid amides RC(=0)NR2 can be prepared from acid halides (or anhydrides) and an amine R2NH. This may often require the preparation of carboxylic acids and of the corresponding acid halides. One may prefer, however, a simple route, involving conversion of the cheap, commercially available (carcino-genous) dimethylcarbamoyl chloride with an organometallic derivative [47] ... 

Carboxylic acid fluorides are not of particular preparative importance since the reactions that can be carried out with them proceed analogously with the cheaper carboxylic acid chlorides. These fluorides are very stable, even towards hydrolysis. Formyl fluoride can be kept at room temperature for several hours before it decomposes into CO and HF. The preparation of carboxylic acid fluorides from the corresponding chlorides and KF was mentioned on page 204. If butyric anhydride is heated gradually to 180° with KHF2, butyryl fluoride, b.p. 67° 1167 mm, distils off, and benzoyl fluoride, b.p. 155-156°, can be obtained analogously from benzoic anhydride at 190-240°. KF can also be used in place of KHF2. Yields are around 80-90%.1079... 

Preparation of Carboxylic Acid Chlorides (and Anhydrides). Oxalyl chloride has found general application for the preparation of carboxylic acid chlorides since the reagent was introduced by Adams and Ulich. Acid chlorides produced by this means have subsequently featured in the synthesis of acyl azides, bromoalkenes, carboxamides, cinnolines, diazo ketones, (thio)esters, lactones, ketenes for cycloaddition reactions, intramolecular Friedel-Crafts acylation reactions, and the synthesis of pyridyl thioethers. ... 

When a solution of a carboxylic acid and an alcohol in pyridine is treated with tosyl chloride, an ester is formed rapidly in excellent yield. This procedure is useful especially in the esterification of tertiary alcohols. The combination of a carboxylic acid and tosyl chloride serves as a convenient method of in situ preparation of symmetrical acid anhydrides for further formation of esters and amides (eq 19). The novelty of this protocol is that the acid can be recycled through the anhydride stage in the presence of the alcohol, thereby resulting in complete conversion to the ester (eq 20). Reactivity is determined hy the strength of the acid strong acids facilitate the esterifications. ... 

General procedure for the preparation of dialkyl H-phosphonates by direct esterification of H-phosphonic acid in the presence of carboxylic acid anhydride (ref DE4,121,696,1991). 

Purpose. One of the important methods for preparing cyclic carboxylic acid anhydrides is carried out. The reaction demonstrates the use of acetic anhydride, an important industrial and research chemical, as a dehydrating agent. 

Although acetyl and other acyl nitrates are dangerously explosive, in solution they undergo smooth thermolysis to alkyl nitrates with one less carbon atom (Scheme 154) a number of methods are discussed for the preparation of acyl nitrates. Thermolysis is conducted at high temperature to minimize the alternative mode of decomposition, production of carboxylic acid anhydrides and dinitrogen pentoxide. 

With this section, we begin a survey of the preparation of carboxylic acid derivatives. Replacement of the hydroxy group in RCOOH by halide gives rise to acyl halides substitution by alkanoate (RCOO ) furnishes carboxylic anhydrides. Both processes first require transformation of the hydroxy functionality into a better leaving group. 

Mathews reaction is a one-pot preparation of carboxylic acids from their corresponding nitriles or amides by a dry hydrolysis with phthalic acid or anhydride in the absence of water and solvent. Excellent isolated yields and selectivity (upto 99%) were attained within short reaction times (typically 30 min) when the reaction was performed under microwave heating (Chemat, 2002). 

This chapter concerns the preparation and reactions of acyl chlorides acid anhydrides thioesters esters amides and nitriles These com pounds are generally classified as carboxylic acid derivatives and their nomenclature is based on that of carboxylic acids... 

Conversion of the carboxylic acid to the diethyl amide interestingly leads to an agent that exhibits the properties of a respiratory stimulant. One synthesis of this agent starts with the preparation of the mixed anhydride of nicotinic and benzene-sulfonic acid (4). An exchange reaction between the anhydride and diethyl benzenesulfonamide affords nikethemide (5). ... 

Acid anhydrides can be derived from two molecules of carboxylic acid by strong heating to remove 1 equivalent of water. Because of the high temperatures needed, however, only acetic anhydride is commonly prepared this way. 

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